2 - (4 -(3&#39;,4&#39; - diphenylcyclopentyl)-phenoxy) lower aliphatic monocarbocyclic acids and esters thereof

ABSTRACT

THE INVENTION RELATES TO 2 - (4-(3&#39;&#39;,4&#39;&#39;-DIPHENYLCYCLOPENTYL)PHENOXY) LOWER ALIPHATIC MONOCARBOCYCLIC ACIDS AND THE CORRESPONDING LOWER ALKYL ESTERS, AND TO A PROCESS FOR THEIR PRODUCTION. THE COMPOUNDS ARE USEFUL AS HYPOLIPIDEMICS.

Patented Aug. 10, 1971 substituted aliphatic acid or ester as illustrated by the fol- 3,598,860 lowing reaction scheme: 2 [4 (3,4 DIPHENYLCYCLOPENTYL)-PHE- NOXY] LOWER ALIPHATIC MONOCARBO- CYCLIC ACIDS AND ESTERS THEREOF 5 [D Rudolf G. Griot, Flor-ham, N.J., assignor to Sandoz-Wander, Inc. No Drawing. Filed July 8, 1968, Ser. No. 743,039

Int. Cl. C07c 39/12, 65/00, 69/76 U U.S. Cl. 260473 3 Claims 1 1 X(IJCOOR R 1 ABSTRACT OF THE DISCLOSURE The invention relates to 2 [4(3',4-diphenylcyclopentyl)phenoxy] lower aliphatic monocarbocyclic acids and the corresponding lower alkyl esters, and to a proc- I v R1 ess for their production. The compounds are useful as GM I I hypolipidemics. R2

(II) (III) (I) This invention relates to derivatives of aliphatic acids. Whefein R1, R2 a are as defined, X TePTeSePtS halogen In particular the invention pertains to 2-[4-(3,4'-diphenylhavmg an a Weight of from 35 t0 7, ChlOfO, cyclopentyl)phenoxy] lower aliphatic monocarbocyclic bromo P lodo, and represents an al'kall-metal P acids and the corresponding lower alkyl esters. The inveny Sodlum or P tion also relates to intermediates useful in preparing said The abPvfi Process 15 convenlenfly Carried out In an acids and esters as well as processes for preparing said an Organic Solvent at elevated temperatul'es- Preferintermediates and i acids and esters ably the reaction is carried out at a temperature of from The substituted aliphatic acids and esters of the present about to about and in Same Solvent invention may be represented structurally as follows: Ployed for the Preparation of the alkfill-metal Salt derlvative of Formula II from the corresponding phenol dis- 30 cussed in further detail hereinafter. The resulting product (I) is readily recovered in conventional manner.

It will be readily appreciated by one skilled in the art that the compounds of Formula I wherein R is hydrogen, i.e., the free acids, may also be obtained from the corresponding esters of Formula I (i.e., where R is alkyl) by simple basic hydrolysis of the ester in conventional manner. The hydrolysis is conveniently carried out by treating the ester with an alcoholic solution of an alkalimetal hydroxide, e.g., potassium hydroxide in methanol. Various of the 2-halo substituted alkanoic acids and esters of Formula III employed in the above-illustrated process are known and can be prepared by methods described in the literature. Such others which may not be I 1 specifically described in the literature can be prepared O+COOR3 from available material in analogous manner.

2 The alkali-metal salts of 4-(3',4'-diphenylcyclopentyl)- (I) phenol (Formula H) are conveniently prepared by reacting the corresponding phenol with an alkali-metal hydride, e.g., sodium hydride or potassium hydride, at room temperature (20-25 C.) in an inert substantially anhydrous organic solvent. Suitable solvents include dimethylacetamide, diethylacetamide and dimethylformamide. As previously indicated hcreinabove the solvent employed in preparing the phenolate is preferably employed in carrying out the subsequent reaction of the phenolate (II) with wherein each of R and R independently represents hydrogen or straight chain lower alkyl preferably containing from 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl, and

y and the appropriate 2-halo substituted alkanoic acid or ester R represents hydrogen or straight or branched chain (11-1) Th preparation f h phengl i 4 (3' 4'-di.

lower alkyl preferably containing from 1 to 4 carphenylcyclopentyl)phenol is illustrated in Example 1 herebon atoms, e.g., methyl, ethyl, propyl, isopropyl or inafter.

butyl. The compounds of Formula I are useful because they possess pharmacological activity in animals. In particular,

The Compounds of Formula I are most Conveniently the compounds are useful as hypolipidemic agents having prepared by reacting an alkali-metal salt of 4-(3,4-dihypocholesteremic and/or hypotriglyceridemic activity,

phenylcyclopentyl)phenol with an appropriate 2-halo as indicated by tests on a group of white rats which are given -50 mg. per kg. of body weight per diem of the compound orally, for six days, followed by extraction with isopropanol of serum or plasma after anesthetizing the rats with sodium hexobarbital, and then noting the cholesterol and triglyceride contents as compared to those of a control group. The cholesterol and triglyceride contents are determined by the methods described by Lofland, H. B., Anal. Biochem. 9: 393 (1964): (Technicon method N 24a); and Kessler, G., and Lederer, H. Technicon Symposi-um, Mediad Inc., New York, pages 345-347 (1965), respectively. For such usage, the compounds may be administered orally as such or admixed with conventional pharmaceutical carriers. The dosage administered may vary depending on the particular compound employed, the therapy desired and the severity of the condition being treated. In general, satisfactory results are obtained when administered at a daily dosage of from about 4 milligrams to about 30 milligrams per kilogram of animal body weight, preferably given in divided doses, 2 to 4 times a day, or in sustained release form. For most mammals the total daily dosage is from about 0.05 gram to about .4 gram of the compound, and the dosage forms suitable for internal use comprise from about 12.5 milligrams to about 200 milligrams of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

For above usages, oral adminstration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethylp-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hardfilled capsules and tablets.

The compounds of Formula I wherein R is hydrogen (i.e. free acids) may be similarly administered in the form of their non-toxic pharmaceutically acceptable salts. Such salts do not materially differ from the free acid forms in their pharmacological eifect and are included within the scope of the invention. As illustrative of such salts there may be included aluminum salt; non-toxic alkali metal salts, e.g., potassium and sodium salts; nontoxic alkaline earth metal salts, e.g., magnesium and calcium salts; salts with N-containing bases such as ammonium salts and pharmaceutically acceptable primary, secondary and tertiary amine salts, e.g., ethanol amine salts, diethanol amine salts, and the like. Such salts are prepared in conventional manner.

A representative formation is a tablet prepared by conventional tabletting techniques and containing the following ingredients.

Ingredient: Weight (mg) 2-methyl-2- [4- (3 ',4'-diphenylcyclohexyl phenoxy]propionic acid 50 Tragacanth 10 Lactose 197.5 Corn starch 25 Talcum 15 Magnesium stearate 2.5

The following examples show representative compounds encompassed within the scope of this invention and the manner in which such compounds are prepared. However, it is to be understood that the examples are for purposes of illustration ony and are not intended as in any way limiting the scope of the invention which is defined in the appended claims.

EXAMPLE 1 2-methyl-2- [4- (3 ,4'-dihphenylcyclopentyl phenoxy] propionic acid ethyl ester Step A.: Preparation of 3,4-diphenyl-1-(4-hydroxyphenyl)-cyclopentan-1-o1.23.6 g. of 3,4-diphenyl-cyclopentan-l-one are added at 20 C. portionwise to 20.0 g. of p-hydroxy-phenylmagnesium bromide, (J.C.S. 93, 71) in 200 ml. of dry diethylether. After stirring at room temperature for 24 hours the reaction mixture is refluxed for another 6 hours. The mixture is cooled to 10 C. and an ice cold saturated solution of ml. of ammonium chloride, is added slowly. The layers are separated and the organic phase washed twice, each time with ml. of a saturated sodium chloride solution. The ether extract is then dried over magnesium sulfate, evaporated to dryness and the resulting crude title compound obtained.

Step B: Preparation of 3,4-diphenyl-1-(4-hydroxyphenyl)-cyclopentane.The crude material from the previous step is dissolved in 75 ml. of glacial acetic acid, 2.0 g. of a catalyst composed of 5% palladium on charcoal are added thereto and the mixture hydrogenated at a temperature of 60 C. under 1500 p.s.i. hydrogen pressure. The hydrogenation is completed in approximately 12 hours and the amount of hydrogen introduced is approximately the stoichiometric amount. The resulting mixture is filtered and the solvent evaporated in vacuo. The residue is taken up in ethyl acetate, washed with sodium bicarbonate 2X 50 ml. then twice with 100 ml.

water and dried over magnesium sulfate. After evaporat-- ing the solvent, the residue is crystallized from hexane.

Step C: Preparation of 2-methyl-2-[4-(3',4-diphenylcyclopenyl)phenoxy] propionic acid ethyl ester.-To 4.8 g. of sodium hydride (50% suspension in mineral oil) suspended in 200 ml. of dry dimethylacetamide is added portionwise with stirring and at room temperature 31.1 g. of 3,4-diphenyl-l-(p-hydroxyphenyl)cyclopentane. To the resulting mixture is added 20 g. of ethyl bromo-isobutyrate and the mixture heated at 100 C. on a water bath for 24 hours. The solvent is then evaporated in vacuo and the residue taken up in 200 ml. of diethyl ether. The ether solution is then washed first with 200 ml. of water, then with 200 ml. of a saturated aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The ether is then evaporated off to obtain 2-methyl-2-[4-(3,4'-diphenylcyclopentyl) phenoxy]propionic acid ethyl ester.

EXAMPLE 2 2-methyl-2- [4- (3 ',4-diphenylcyclopentyl -phenoxy] propionic acid A mixture of 9 g. of 2methyl-2-[4-(3',4'-diphenylcyclopentyl)-phenoxy]propionic acid ethyl ester, 2.0 g. of potassium hydroxide and 40 ml. of methanol is allowed to stand at room temperature for 3 days. The solvent is then evaporated in vacuo and the residue dissolved in water. The resulting solution is extracted twice with 50 ml. (each) of diethyl ether, and the combined ether extracts then acidified with 20 ml. of 2 N hydrochloric acid and extracted three times with 50 ml. (each) of a saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous magnesium sulfate and the solvent evaporated to obtain 2-rnethyl-2-[4 (3',4'-diphenylcyclopentyl)-phenoxy]pripionic acid.

What is claimed is:

1. A compound of formula R1 o-icoom 6 wherein each of R and R independently represents hydrogen or straight chain lower alkyl and R represents hydrogen or straight or branched chain 5 lower alkyl, or, when R represents hydrogen, the

pharmaceutically acceptable salts thereof.

2. A compound of claim 1 which is 2-rnethyl-2-[4-(3', 4'-diphenylcyclopentyl)phenoxy]propionic acid or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 which is 2-methyl-2-[4-(3', 4' diphenylcyclopentyl)phenoxy1propionic acid ethyl ester.

References Cited JAMES A. PATTEN, Primary Examiner J. F. TERAPANE, Assistant Examiner US. Cl. X.R. 

